THE ASSOCIATION OF DEPRESSION WITH PLATELET ACTIVATION: EVIDENCE FOR A TREATMENT EFFECT

Abstract

Summary. Background: Depression is associated with anincreased risk of cardiovascular disease (CVD). Although themechanism is uncertain, prothrombotic and inflammatoryfactors may play a role. Objectives: As platelets play a key roleinCVD,wedeterminedfirst,whetherdepressedindividualshadmore activated platelets than non-depressed individuals andsecond, whether treatment of depression reduced plateletactivation levels. Patients/methods: We recruited 108 depressedoutpatients and 45 control subjects all without a history ofCVD. After psychological assessment, the depressed patientswere offered treatment with medication and/or psychotherapy.Flow cytometric markers of platelet activation and level ofdepression were assessed at baseline and at 4 weeks and6 months after treatment. Results: Depression was associatedwith increased platelet activation with a higher number ofcirculating CD62p (0.76 · 10 9 L )1 vs. 0.46, P=0.019) andCD63 (P = 0.05) positive platelets compared with controls.Patients with depression also had more circulating platelet-leukocyte aggregates than controls (P<0.001). There was apositive correlation between the severity of depression and thelevel of platelet activation. Platelets from depressed patientswere also hyperreactive to adenosine 5´-diphosphate (ADP)stimulation with increased CD62p and CD63 exposure(P=0.003 and 0.019, respectively). Six months of treatmentresulted in a reduced number of circulating CD62p and CD63positive platelets (29.84% and 53.38% decrease) and a 20.9%reductioninCD63exposureafterADPactivation. Conclusions:Depression is associated with increased in vivo platelet activa-tion and resolution of depression using psychotherapy and/ormedication reduces platelet activation. These findings provideinsights into the link between depression and cardiovascularrisk.Keywords: coronary artery disease, depression, plateletactivation.IntroductionCardiovascular disease (CVD) is the major cause of death indeveloped countries. The major risk factors are well identified;however, the role of psychosocial factors requires furtherexploration[1–4].Thepathophysiologicalmechanismbywhichdepression contributes to CVD has not been fully explained.Reputed mechanismsincludereducedvagal tone andincreasedheart rate variability[5,6], increased platelet aggregability [7],impaired endothelial function [8] and more recently increasedinflammation as indicated by C-reactive protein, interleukin-6and intracellular adhesion molecule-1 [9,10].Most acute ischemic events in the coronary circulation areassociated with the process of atherothrombosis [11] andplatelets contribute to both atherosclerotic plaque formation[12] and the atherothrombotic complications associated withplaque instability [13].A number of studies suggest that depression is accompaniedby increased platelet activation [7,14,15]. Walsh et al. alsoreported an increase in the expression of the platelet adhesionreceptor glycoprotein-Ib [16]. Studies have also shown thatselective serotonin reuptake inhibitors (SSRIs) reduced plateletactivation in depression [15,17,18] and that individuals withboth depression and CVD show improved platelet functionwhen treated with SSRIs [19–22]. However, the evidence is notunequiovocal and shows inconsistencies [23,24]. Von Kanelconcluded that data on platelet activity in depression areinconclusive and suggested larger prospective studies [23].Given the importance of thrombosis, we hypothesized thatdepression would be associated with increased platelet activa-tionandthatalleviationofdepressionwouldreducethelevelofplatelet activation. The goals of the present study were first, to